Purification of semi-synthetic paclitaxel and docetaxel, which are well known and approved chemotherapeutic drugs for treatment of metastatic cancer, is a challenging problem due to formation of a number of degradation products along the synthetic route. Furthermore, purified taxanes are found to undergo degradation, even under controlled storage condition. Therefore, it becomes desirable to develop stable crystalline forms of these molecules, which retain the desirable anti-cancer properties. Towards this end Rhone-Poulenc Rover, S.A., France has developed processes for preparation of trihydrates of paclitaxel and docetaxel. According to Authelin et al, U.S. Pat. No. 6,022,985 stability studies have shown that docetaxel trihydrate is stable at 4° C., 25° C., and 35° C. in an atmosphere with 90% relative humidity upto 18 months without modification in its crystalline form. Under similar condition, anhydrous docetaxel slowly changes its crystalline form to the trihydrate form. This U.S. Patent describes a process for the preparation of docetaxel trihydrate by crystallization of anhydrous docetaxel from a mixture of water and an aliphatic alcohol containing 1-3 carbon atom, specifically ethanol. The water/alcohol weight ratio used in this innovation is about 2/1. The crystals obtained thus, are dried under defined condition of temperature (about 40° C.), pressure (4-7) kPa and relative humidity of about 80%. The crystallization was also performed in the presence of ascorbic acid.
In U.S. Pat. No. 6,197,980 to Durand et al., a process for centrifugal partition chromatography of crude docetaxel in two partially miscible phases using an aliphatic hydrocarbon, an ester, an alcohol and water, is described. Docetaxel trihydrate is obtained by concentrating the column fractions. The process did not specify drying conditions.
Similarly paclitaxel trihydrate is reported to have markedly superior stability in comparison to the anhydrous product. (Authelin el al U.S. Pat. No. 6,002,022). According to this invention, paclitaxel trihydrate is obtained from a mixture of water and an aliphatic alcohol containing upto three carbon atoms, specifically methanol. The water/alcohol weight ratio used in this process is between 3/1 to 1/3. The crystals, thus obtained, are dried at about 40° C. under reduced pressure.
Both the U.S. Pat. Nos. 6.022,985 and 6,002.022 are limited in scope, in terms of solvents that could be used for crystallization. Both use aliphatic alcohols containing 1-3 carbon atoms as the solvent of choice. In addition, paclitaxel or docetaxel used for crystallization has to be chromatographed beforehand. Furthermore, the drying conditions used in these patents are specific and recommended conditions are not easy to maintain. In view of the above we have developed a process, for preparation of paclitaxel trihydrate and docetaxel trihydrate, which do not require chromatography. Instead, we use solvent—based purification technique, which is faster, cheaper, and can be scaled up easily. We also found that the choice of solvents in the crystallization of paclitaxel or docetaxel is not necessarily limited to alcohols and aliphatic nitriles are as effective as alcohols.